Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer's Disease: 11 C-Synthesis and In Vivo Proof of Concept

• Published in: Journal of medicinal chemistry 2022-01, Vol.65 (2), p.1342-1351
• Main Authors: Giglio, Javier, Fernandez, Soledad, Martinez, Ana, Zeni, Maia, Reyes, Laura, Rey, Ana, Cerecetto, Hugo
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - diagnostic imaging; Alzheimer Disease - drug therapy; Animals; Brain - drug effects; Brain - metabolism; Carbon Radioisotopes - metabolism; Female; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Humans; Male; Maleimides - chemistry; Mice; Mice, Inbred C57BL; Mice, Transgenic; Positron-Emission Tomography - methods; Proof of Concept Study; Protein Kinase Inhibitors - pharmacology; Radiochemistry; Radiopharmaceuticals - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00769

Herein we present the evaluation of C-labeled-maleimides as radiotracers for positron emission tomography imaging of GSK-3 associated with Alzheimer's disease (AD). 3-Acetyl-4-(1-[ C]-methyl-1 -indol-3-yl)[1 ]pyrrole-2,5-dione ([ C]- ) was obtained by direct methylation using [ C]-CH I and Cs CO in DMF with a 31 ± 4% radiochemical yield and a radiochemical purity of 97.7 ± 0.8%. [ C]- was stable both in its final formulation and in human plasma for 120 min and had a plasma protein binding of 70 ± 1% and a LogD value of 1.84 ± 0.04. [ C]- biodistributions in healthy animals demonstrated significant brain uptake and retention, showing its ability to penetrate the intact blood-brain barrier. PET imaging in mice bearing AD showed, with respect to normal animals, significant differences in uptake in the hypothalamus, the striatum, and the amygdala and a significant increase in amygdala uptake in later stages of the pathology. These results are very promising, and further studies are being performed for a complete validation of this compound as novel tracer for AD.